The present invention relates to the interstitial delivery of particulate drug delivery systems for large and small molecule therapeutic agents within the heart.
Local drug delivery provides many advantages. Approaches for local controlled release of agents at a depth within a tissue such as the heart, pancreas, esophagus, stomach, colon, large intestine, or other tissue structure to be accessed via a controllable catheter will deliver drugs to the sites where they are most needed, reduce the amount of drug required, increase the therapeutic index, and control the time course of agent delivery. These, in turn, improve the viability of the drugs, lower the amount (and cost) of agents, reduce systemic effects, reduce the chance of drug-drug interactions, lower the risk to patients, and allow the physician to more precisely control the effects induced. Such local delivery may mimic endogenous modes of release, and address the issues of agent toxicity and short half lives.
Local drug delivery to the heart is known. In U.S. Pat. No. 5,551,427, issued to Altman, implantable substrates for local drug delivery at a depth within the heart are described. The patent shows an implantable helically coiled injection needle which can be screwed into the heart wall and connected to an implanted drug reservoir outside the heart. This system allows injection of drugs directly into the wall of the heart acutely by injection from the proximal end, or on an ongoing basis by a proximally located implantable subcutaneous port reservoir, or pumping mechanism. The patent also describes implantable structures coated with coating which releases bioactive agents into the myocardium. This drug delivery may be performed by a number of techniques, among them infusion through a fluid pathway, and delivery from controlled release matrices at a depth within the heart. Controlled release matrices are drug polymer composites in which a pharmacological agent is dispersed throughout a pharmacologically inert polymer substrate. Sustained drug release takes place via particle dissolution and slowed diffusion through the pores of the base polymer Pending applications Ser. No. 08/8816850 by Altman and Altman, and Ser. No. 09/057,060 by Altman describes some additional techniques for delivering pharmacological agents locally to the heart. Implantable drug delivery systems, such as controlled release matrices, have been well described in the literature, as has the use of delivering particulate delivery systems or particulate drug carriers such as microcapsules, lipid emulsions, microspheres, nanocapsules, liposomes, and lipoproteins into the circulating blood. However, local delivery of such micro drug delivery systems to a depth within the myocardium using endocardial catheter delivery and epicardial injection systems have not been described, and have many advantages that have not been foreseen.
Recently, local delivery to the heart has been reported of therapeutic macromolecular biological agents by Lazarous [Circulation, 1996, 94:1074-1082.], plasmids by Lin [Circulation, 1990; 82:2217-2221], and viral vectors by French [Circulation, Vol. 90, No 5, November, 1994, 2414-2424] and Muhlhauser [Gene Therapy (1996) 3, 145-153]. March [Circulation, Vol. 89, No 5, May 1994, 1929-1933.] describe the potential for microsphere delivery to the vessels of the heart, such as to limit restenosis, and this approach has also been used for the delivery of bFGF by Arras [Margarete Arras et. al., The delivery of angiogenic factors to the heart by microshpere therapy, Nature Biotechnology, Volume 16, February 1998. These approaches for microsphere delivery obstruct flow, and will be delivered preferentially to capillary beds which are well perfused. Further, these approaches do not deliver therapeutic agents to the interstitial spaces. None of this work recognizes the potential to use particulate drug delivery system to optimize local drug delivery at a depth within the myocardium. This art also does not recognize the potential such delivery systems have in treating disease substrates in the myocardium if delivered to an appropriate region of the myocardial interstitium.
Problems exist for delivering small molecules or lipophilic molecules which rapidly transport through the capillary wall, to well-perfused tissues such as the myocardium. These problems are due to the convective losses of the agents to the systemic circulation. By going rapidly across the capillary wall, the small molecules are rapidly carried away by the bloodstream. Local delivery of an easily transported molecule is difficult because local delivery concentrations are rapidly reduced at very small distances from the delivery site due to convective losses. Such easily transported agents cannot treat an effective area of tissue locally without raising the systemic concentrations of the agents to a therapeutic level.
The therapeutic compounds described below comprise very small capsules which can be injected into body tissue, particularly the heart. The capsules include an encapsulating layer which surrounds a therapeutic agent. After injection, the encapsulating layer degrades or dissolves, and the therapeutic agent is released within the heart. The therapeutic agent may be one of any number of known agents such as anti-arrhythmic drugs, gene therapy solution, and macromolecules intended to have either acute or long term effects on the heart. While some of these therapeutic agents are used to treat the heart by injecting them into the heart, they are of such small size that they readily enter the cardiac capillary system and the cardiac lymphatic system, and are quickly transported away from the injection site. Thus, in prior treatment methods, relatively large doses and repeated doses are required to provide therapeutic effect at the injection site. To provide a solution to this problem, the capsules described below are provided in sizes that are too large to permit capillary transport or lymphatic transport. Thus, injected capsules are immobile within the heart tissue, and upon degradation they will release a therapeutic agent very near the site of injection. The capsules may also be provided in sizes that are too large to permit capillary transport, but small enough to enter the lymphatic system and be transported away from the injection site in the cardiac lymphatic system, so that the therapeutic effect is provided at some distance from the injection site. The encapsulating layer may be made from various materials including biodegradable polymers in the form of microspheres, or from standard vesicle forming lipids which form liposomes and micelles.